The Significance Of Advanced Glycation End Products In Fracture Risk Assessment Of Postmenopausal Type 2 Diabetes Mellitus

Objective:Based on the characteristics of the patients with Type 2diabetes mellitus(T2DM),we adjusted the Fracture risk assessment tool(FRAX~?)recommended by the WHO.To explore the potential clinical significance of advanced glycation end products(AGEs)in assessing fracture risk in postmenopausal T2DM patients,the quantitative relationship between AGEs and adjusted FRAX value(FRAX-RA)in postmenopausal T2DM patients was evaluated,and the critical value of AGEs for fracture risk prediction was analyzed.Moreover,the relationships between serum AGEs level and bone turnover markers,blood glucose-related indexes and inflammatory factors were also analyzed.Methods:1.Subjects:180 postmenopausal T2DM patients treated in the Second Department of Endocrinology,the Third Hospital of Hebei Medical University from October 2019 to May 2020 were selected as diabetes mellitus group(DM group);186 people received physical examination were selected as the none DM group(NDM group).Bone mineral densities(BMDs)of all subjects were measured by Dual energy X-ray absorptimometry(DXA).The criterions included:(1)the age of 45-80 years old women with independent activity ability,menopause(including natural menopause or menopause by surgery after 40 years old)for more than 3 years;(2)T2DM was diagnosed and classified by the WHO criterions(1999).(3)Osteoporosis was diagnosed according to the WHO diagnostic criterions.Strict exclusion standards were also formulated.According to the criterions metioned above,180 T2DM subjects were divided into 3 groups:DM patients with normal bone mass(DMN group,52 cases),DM patients with osteopenia(DMOPN group,60cases)and DM patients with osteoporosis(DMOP group,68 cases);186people received physical examination were divided into 3 groups:normal group(Control group,58 cases),osteopenia group(OPN group,63 cases),osteoporosis group(OP group,65 cases).2.Data collection:General clinical datas of all subjects(including age,menopausal age,weight,height,and BMI)were collected;Fasting plasma glucose(FPG),Fasting insulin(FIns),Glycosylated hemoglobin(Hb A1c)were tested.The Homeostasis model assessment of insulin resistance index(HOMA-IR)was calculated by the formula:HOMA-IR=FPG*Fins/22.5.In addition,serum AGEs,insulin,25-hydroxyvitamin D3(25-OHD3),Procollagen type I N-peptide(PINP),Serum C-terminal telopeptide of type I collagen(S-CTX),Interleukin-1β(IL-1β),IL-6,Tumor necrosis factor-α(TNF-α)and Transforming growth factor-β(TGF-β)level were detected by Enzyme-linked Immunosorbent Assay(ELISA).3.Statistical analysis:The relationship between AGEs and corrected FRAX values was analyzed by the Pearson or Spearman correlation;the relationship between AGEs and bone turnover markers,blood glucose indexes and inflammation indexes were also analyzed by the Pearson or Spearman correlation.The cut point value of AGEs was explored by the receiver operator characteristic curve(ROC)to clarify the significance of AGEs in the fracture risk assessment in postmenopausal T2DM patients.Results:1.There was no significant difference in age and years of menopause between DM and NDM group(P>0.05),but the BMI level of DM group was significantly higher than NDM group(P<0.05);The BMI level of DMOP group was significantly lower than DMN and DMOPN group(P<0.05);The BMI level of OP group was significantly lower than Control and OPN group(P<0.05);2.The BMD values of lumbar spine and both hips in DM patients were significantly higher than NDM group(P<0.05).Firstly,the unadjusted FRAX values were used to assess the fracture risk of T2DM patients.We found that the probabilities of major osteoporotic fracture(MOF)and hip osteoporotic fracture(HF)of T2DM patients were significantly lower than NDM group(P<0.05).Then,we adjustd the FRAX values of T2DM patients by rheumatoid arthritis(RA)equivalent variable to get MOF-RA and HF-RA.The level of MOF-RA in DM group was higher than NDM group(P<0.05);there was no significant difference in HF-RA between two groups,but HF-RA value in DM group tended to be higher than NDM group;3.The level of AGEs in DM group was significantly higher than NDM group(P<0.05);4.Pearson correlation analysis showed that the level of AGEs in postmenopausal T2DM patients was positively correlated with MOF-RA(r=0.6819,P<0.0001)and HF-RA(r=0.6768,P<0.0001),respectively;5.Serum PINP level in DMOP patients was significantly lower than DMN and DMOPN groups,and S-CTX level in DMOP patients was significantly higher than DMN and DMOPN groups(P<0.05),but there was no significant difference of serum 25-OHD3 level among the three groups(P>0.05);6.There was no significant difference of FBG,Hb A1c,insulin and HOMA-IR among DMN,DMOPN and DMOP group(P>0.05);7.Serum IL-6 and TGF-βlevels in DMOP group were significantly higher than DMN and DMOPN group(P<0.05),while there was no difference of serum IL-1βand TNF-αlevels among the three groups(P>0.05);8.Spearman correlation analysis showed that there was a negative correlation between AGEs and PINP in postmenopausal T2DM patients.Pearson correlation analysis showed that there was a positive correlation between serum AGEs and S-CTX in postmenopausal T2DM patients,but not correlated with 25-OHD3;9.Spearman correlation analysis showed that AGEs level in postmenopausal T2DM patients was positively correlated with FBG,Hb A1c and HOMA-IR,but not correlated with insulin;10.Pearson correlation analysis showed that the level of AGEs in menopausal T2DM patients was positively correlated with IL-6 and TGF-β,but not correlated with IL-1βand TNF-α;11.The ROC curve analysis showed that AGEs may be an important reference index for predicting fracture risk in postmenopausal T2DM patients.Conclusions:1.BMD measured by DXA and the uncorrected FRAX value can not truly evaluate fracture risk of T2DM patients,so the FRAX value needs to be adjusted.2.As an important indicator of non-enzymatic cross-linking of bone collagen molecules in postmenopausal T2DM patients,AGEs has a linear correlation with the corrected FRAX value(FRAX-RA);AGEs was negatively correlated with serum PINP and positively correlated with serum S-CTX;there was a positive correlation between AGEs and serum IL-6、TGF-βin postmenopausal T2DM patients.3.The threshold value of AGEs for predicting fracture risk in postmenopausal T2DM patients was 4.1561 mmol/L.